The ultimate goal of this SBIR proposal is to develop novel radiopeptides as targeting agents for internal radiotherapy of prostate cancer. Prostate cancer is the most common cancer affecting men in the United States. Currently, early stage prostate cancer is treated with surgery, external beam radiation or radioactive seed implants. Hormonal therapy, chemotherapy and radiation are used for the treatment of advanced disease. However, no effective treatment is available for androgen independent prostate cancers. Significant effort has been expanded in attempts to develop radiolabeled antibodies for therapeutics purposes. Clinical applications of these radiolabeled macromolecules have generally been unsatisfactory due to low tumor specificity of targeted epitopes, limited penetration into tumors, and the provocation of anti-mouse immunoglobulin responses. These considerations favor the use of nonimmunogenic small molecules with higher uptake in tumors. These criteria are fulfilled by peptides. Some peptides such as gastrin releasing peptide (GRP) and its receptor has been found highly expressed in tumor cells, including prostate, breast, gut and pancreas. Recently, bombesin (BBN) peptide derivatives have been labeled with 177Lu and 90Y for prostate cancer therapy with promise. Despite the success of such approaches, these peptide tracers have relatively low tumor uptake and retention in prostate cancer and suboptimal in vivo kinetics. We recently developed the concept of dual receptor targeting. We designed a BBN-RGD peptide heterodimer that binds to both GRPR and integrin ?v?3, which showed outstanding tumor targeting efficacy and imaging characteristics. Dual-receptor binding results in more than an additive effect in vivo in terms of tumor uptake and retention in an androgen-receptor (AR)-negative PC-3 tumor model. Therefore, in this SBIR proposal, we would like to extend this concept to develop a clinically translatable peptide receptor targeted radiotherapy (PRTR). The first six- month phase I of this proposal will focus on developing and synthesizing the peptide radiotracers and in vitro characterization for their receptor binding affinity, hydrophilicity and cytotoxicity. The second phase of the proposal will focus on the pharmacokinetics and pharmacodynamics of the radiotracers. Mouse dosimetry of therapeutic 90Y-labeled BBN-RGD peptides will be calculated. The maximum tolerable dose (MTD) for 90Y- labeled BBN-RGD radiopharmaceuticals will be determined by dose escalation studies. Treatment efficacy on different tumor models will be assessed. The innovation in this proposal is developing a novel strategy which provides exciting promise to develop efficient targeted radiotherapy products that can be applied to various types of cancers. PUBLIC HEALTH RELEVANCE: We will develop the novel clinically translatable dual integrin and GRPR targeted radiotherapy of prostate cancer. Because the agent targets preferentially to specific receptors on cancer cells, we anticipate that the new tracers for radiotherapy will have better efficacy and reduced peripheral toxicity. The same strategy should also be applicable to other cancer therapeutics.